Use in single pill/tablet/capsule of minocycline, fluconazole and atorvastatin in the treatment of multiple sclerosis

ABSTRACT

The present invention has for object the use of minocycline or its equivalent forms, or of any form of tetracycline in combination with Fluconazole or any of its equivalent form with antifungal capacity and atorvastatin or any equivalent form (lipophilic statins) for the preparation of a single compound directed to the treatment of every type of multiple sclerosis or diseases etiopathologically equivalents, whether it be of remitting relapsing or progressive, but anyway degenerative kind, considering the weaker of subject that will receive it as consequence of previous treatments or state of illness. The effectiveness of this combination has been shown from many researches on single components. 
     To date, given the proven efficacy of the individual components, the low toxicity of the same and the long period of the marketing thereof, as well as the observed greater efficiency of the combination of the same used in accordance with the overexposed new mode of use, it can be said that the above-mentioned new compound derived from a combination of minocycline or its equivalent forms, or of any form of tetracycline in combination with Fluconazole or any of its equivalent form with antifungal capacity and atorvastatin or any equivalent form (lipophilic statins), is effective in reduce the incidence of the disease on quality of life of the patient with the designed dosage that never has been determined before.

TECHNICAL FIELD

New pharmacological combination in treatment of multiple sclerosis disability and dosage.

The present invention has for object the use of minocycline or its equivalent forms, or of any form of tetracycline in combination with Fluconazole or any of its equivalent form with antifungal capacity and atorvastatin or any equivalent form (lipophilic statins) for the preparation of a single compound directed at the treatment of autoimmune-type forms of multiple sclerosis or diseases with common origin, whether it be for relapsing remitting, progressive or degenerative form.

BACKGROUND ART

Multiple sclerosis affects the nerve cells, making it difficult to communicate between the brain and spinal cord. Nerve cells transmit electrical signals, called action potentials, through long fibers called axons, which are covered with an insulated substance, the myelin sheath. In this disease, the patient's immune defense system attack and damage this sheath. When this happens, the axons are no longer able to transmit signals effectively. The name derives from multiple sclerosis scars (sclerosis, better known as plaques or lesions) that are formed in the white matter of the spinal cord and brain. Although the mechanism by which the disease occurs is well understood, the exact etiology is still unknown. The different theories propose causes both genetic and infectious; are also highlighted correlations with environmental risk factors.

The disease can manifest with a wide range of neurological symptoms and can progress to total physical and cognitive disability, to date with clinically assessed EDSS (Expanded Disabilty Status scale). Multiple sclerosis may take several forms, including relapsing and progressive ones.

Until date 2014 there is no known cure. Some drug treatments are available to prevent new attacks, and prevent disability. The prognosis is difficult to predict and depends on many factors, while the life expectancy is approximately from 5 to 10 years lower than that of the healthy person.

The patient usually sees reduction in the regenerative capacity of his body with each new acute episode, which to date is treated with nonsteroidal anti-inflammatory drugs (corticosteroids administered in the form of bolus injections, inframuscolar or orally). In quiescence periods between one episode and another, in general are administered immunosuppressive or immunomodulatory treatments, that would be suspended during the acute phases.

To date, all proposed treatments to cope with this disease have a number of serious side effects and carriers of a constant weakening of the body, without providing any form of real recovery or re-balancing of the body.

Below are overviews of the current most used therapies and their side effects:

Monoclonal Antibodies

Some drugs such as Natalizumab (monoclonal antibodies) can cause side effects with almost certainly fatal outcome (PML), for which when are developing specific antibodies must be suspended because they generate in almost all patients a rebound effect. The benefits obtained whith natalizumab are canceled and generally the situation is greatly pejorative.

Interferons

People with MS taking interferon may experience side effects. Most of the side effects are the same for the different interferons used in the treatment of relapsing remitting multiple sclerosis (interferon beta-1a: Avonex, Rebif, interferon beta-1b: Betaferon). Many side effects are associated with every interferon alone, or have different frequency depending on the type.

Immunomodulatory

An immunomodulatory drug is the copolymer 1 or glatiramer acetate (Copaxone®), which consists of a mixture of amino acids which simulates the composition of a protein of myelin, thus reducing the reaction of the immune system against the myelin of the nervous system. Interferons and glatiramer have comparable efficacy, the benefit of glatiramer is to have fewer side effects of interferon therapy and to be generally well tolerated, but in any case does not seem to have an effect on the incidence of relapses, do to improve the quality of life of the patient as well as being strongly not-recommended in case of pregnancy, in this case should be discontinued.

Emerging Therapies in Multiple Sclerosis

They're going to get or are just on the market a number of new drugs for the prevention of relapse. Unfortunately they are problematic for their safety profiles.

Dimethyl fumarate (Tecfidera®): a new drug for multiple sclerosis taking orally with good efficacy, probably better than that of interferons and glatiramer acetate. Being a derivative of normal cellular metabolism seems to have a good safety profile. However, it has frequent side effects such as skin reactions (flushing/redness), and gastrointestinal disorders.

Teriflunomide (Aubagio®), an oral medication that can be used in place of interferons or glatiramer acetate in relapsing-remitting MS. Has probably comparable efficacy and is a molecule already widely used in rheumatology in the form of its precursor levoflunamide. Its main advantage is the ease of use: no more injections, but only one oral capsule daily. The disadvantages are the potential hepatotoxicity with the need for monthly checks of liver transaminases and a very prolonged elimination time, up to 2 years. There are methods to accelerate the elimination of the drug, which may be used for example in the case of a pregnancy designed. Unplanned pregnancies should be avoided for the teratogenic potential of the drug and did not exclude the difficulty of elimination in the case of an unplanned pregnancy.

Alemtuzumab (Lemtrada®): anti-lymphocytes leading to significant depletion of T and B lymphocytes in the circulation. Used for years in the treatment of chronic leukemia, has been withdrawn from the market in 2012 only to be reintroduce for multiple sclerosis with an increased price (the same method used in the recent case Avastin-Lucentis). It has high efficiency, but also frequent and serious side effects: approximately 40% of patients develop thyroid autoimmune diseases, hematologic and renal complications were causes of death during clinical trials. The treatment therefore requires a precise monitoring program with monthly checks of the blood and urine examination, which must be planned for 4 years after the last infusion. The scheme of therapy consists of a series of 5 daily infusions at the beginning and 3 infusions after a year. For sustained and prolonged immunosuppressive activity its not a therapy that can be terminated or modified easily and it is not clear today how to proceed in case of insufficient response to therapy. Alemtuzumab can be used only in patients with very active disease as defined in clinical or radiological exams. It should not be used for those who have a stable path or has no signs of active inflammation in MRI. It's a therapeutic tool in most, however, reserved for serious situations after careful evaluation and informing patients about the risks and monitoring requirements associated with its use. With regard to safety and also the real benefit of the drug, the Food and Drug Administration (FDA) has recently expressed strong doubts requesting a review of the approval process for the time being denied in the United States. According to FDA reviewers, alemtuzumab is associated with serious safety problems, potentially fatal, which could make this drug non-approvable in the United States.

Laquinimod: Clinical studies are still underway to complete the request for permission. It's an oral immunomodulator with a good safety profile and activity probably comparable to interferons. The mechanism of action is only partially known. Are underlined its possible neuroprotective properties and neuroimaging studies are underway to evaluate their effectiveness in slowing brain atrophy.

Since November 2011 is available in Italy the first immunomodulatory drug for oral fingolimod, for now it's restricted to patients with relapsing-remitting MS with high disease activity despite treatment with beta interferon, or in patients with severe forms of the disease rapidly evolving. Requires special precautions for possible side effects liver, cardiac and eyes.

CCSSVI-“Zamboni method”

Very controversial from the beginning, the role of a possible venous insufficiency (CCSVI), which seems to be present even in healthy people and in other neurological disorders. The experience CCSVI can now be considered complete, at least on an international basis. Results described initially by Zamboni's group have not been replicated by many other groups despite a strong interest. In the recent ECTRIMS congress in Copenhagen, one of the most important conferences on multiple sclerosis, of more than 1000 contributions, only four dealt with CCSVI, describing only negative results and, in the case of angioplasty, rather subjective and not long-lasting effects. In the conclusion CCSVI is more of a hypothesis that has received huge attention from the Internet, boosted after the publication and with effects not reproducible.

Other Drugs

In special situations, other immunosuppressive drugs (azathioprine, methotrexate, cyclophosphamide) are also used that block cell replication globally, thus slowing down the reaction of the immune system. Being potentially toxic drugs, also used in cancer chemotherapy, are reserved for cases of multiple sclerosis with rapid progression and disabling who do not respond adequately to an immunomodulatory drug. The selection, prescription and monitoring of immunomodulatory and immunosuppressive therapies (chemotherapics very impactful as mitoxantrone) requires special expertise and is (even for the high cost of treatment) allocated to the centers for multiple sclerosis.

Multiple sclerosis is a frequent cause of acute and chronic disability in young and middle-aged people. Usually occurs for the first time between 15 and 50 years with a peak incidence in young adults, affecting twice as many women than men. There is no known specific cause, though genetic factors seem to be involved in the predisposition to develop the disease. Even prior viral infections may represent a risk factor, now seems increasingly evident role of the Epstein-Barr virus responsible for mononucleosis.

DISCLOSURE OF INVENTION

As a result of a study conducted by today's applicant, in turn, affected by multiple sclerosis diagnosed over 20 years, based on a combined reading of some research which are summarized below for the sake of knowledge has been tested with unexpected and surprising success (reduction of the value found in EDSS by at least 2 points, stable after 2 years without further dosing) a combination of three pharmacological substances (whose patents have yet expired): Minocycline or its equivalent forms, or of any form of tetracycline in combination with fluconazole or any of its equivalent form with antifungal capacity and atorvastatin or any equivalent form (lipophilic statins) in a single solution.

The research used:

To date, the most commonly used therapies in the treatment of multiple sclerosis (MS), is intended to solve the immunological aspects. But despite the progress made, many patients do not respond well to these drugs.

Is therefore necessary to develop new pharmacological strategies. Animal studies with which we began has focused on mouse models, in which was induced MS called experimental autoimmune encephalomyelitis (EAE). The research results have shown some important evidence.

In mice studied, the combined use of two molecules (atorvastatin and minocycline) has led to improvements both clinical and immunological; In fact, there was a significant anti-inflammatory and neuroprotective activity.

The drug not only reduces the severity and histological consequences in mice but slows the progression of the disease. Everything is confirmed and accompanied by a visible reduction of the areas of brain lesion in a percentage that comes to 40%.

However, the novelty of what is required as patent resides in having identified over to the actual operation of the two above-mentioned molecules in association with each other (which when combined produce a different effect, and much higher than that of the individual), although their effective dosage in the administration, shown below, as well as the effectiveness of the combination with fluconazole, able to drastically reduce the possibility of developing poisoning given by a potential out of control proliferation of candida albicans in subjects who were treated with minocycline, which, as an antibiotic, could determine the onset.

In any case, the most important finding verified by the applicant of this patent, derived from six subjects with MS, who have agreed to test (under constant medical monitoring and after having signed an appropriate confidentiality agreement) such therapy on themselves to assess their effectiveness, given the evident improvement obtained by the applicant. All subjects showed a significant functional recovery as early as the first week of administration, which also extends over time even after suspending the therapy, lasting 45 days.

The administration in all cases studied had a further increase in efficacy when the two molecules mentioned above was added, always under medical control, in the use of fluconazole which has allowed to nearly zero the only side effect given by an increase in abdominal volume most likely caused by the use of prolonged minocycline that, as an antibiotic, may have produced an increase in the proliferation of Candida albicans, further cause of worsening of the clinical condition in the pathology of which is comes.

To date, all parties involved have a significant improvement in quality of life, having recovered much of its autonomy, which still has to be considered in relation to the starting point of taking drug based on the EDSS. In any case in industrial production the potential side effects, warnings and precautions for use must be indicated.

Best Mode for Carrying Out the Invention

The dosage of treatment applied and suggested was the following: intake for 45 days a combination of minocycline 100 mg, 20 mg of atorvastatin, 50 mg of fluconazole, included in a single capsule to be taken, considering the half-life of the drug, every 12 hours.

There were no noteworthy side effects and since the first week of administration has been observed functional recovery clinically confirmed by the administration of test and evaluation boards (Scale Bartel Index, Analysis of muscle imbalance Kendall, Walking test 2MWT).

The best way to prepare it, also for an hypothetical industrial applicability, seem to create a gastroresistant capsule that will include all the three active substances.

In a subject has been observed through magnetic resonance as there has been a remission of demyelinated areas on account of approximately 40%.

None of the above medications interacted negatively with any medication already used by patients, none of them has had any relapse during the treatment.

To date, given the proven efficacy of the individual components, the low toxicity of the same and the long period of permanence in the market thereof, as well as the observed greater efficiency of the combination of the same used in accordance with the new model of use overexposed, it can be said that the above-mentioned new compound derived from a combination of minocycline or its equivalent forms, or of any form of tetracycline in combination with Fluconazole or any of its equivalent form with antifungal capacity and atorvastatin or any of its equivalent form (lipophilic statins) is effective in reducing the incidence of the disease on quality of life of the patient.

It is not yet know if it affects the number of relapses but to date none of those involved had neither worsened acute episodes, so it seems to be a promising treatment, however, also in view of future therapeutic developments. 

1. Use under medical control and prescription of minocycline or its equivalent forms, or of any form of tetracycline in combination with fluconazole or any of its equivalent form with antifungal capacity and atorvastatin or any equivalent form (lipophilic statins) for the preparation of a single compound directed at the treatment of autoimmune-type forms of multiple sclerosis or diseases with common origin to take through a pill, capsule or tablet;
 2. Use under medical control and prescription of the combination of minocycline (100 mg) every 12 hours or its equivalent forms, or of any form of tetracycline, atorvastatin (20 mg) every 12 hours or any equivalent form (lipophilic statins) and fluconazole (50 mg) every 12 hours or any of its equivalent form with antifungal capacity, or their physiologically acceptable forms for the preparation of an oral medicament, in a single tablet or by summation of the three individual substances, for the improvement of quality of life in patients with multiple sclerosis, in whatever form it manifests itself;
 3. Use under medical control and prescription of the combination of minocycline (100 mg) every 12 hours or its equivalent forms, or of any form of tetracycline, atorvastatin (20 mg) every 12 hours or any equivalent form (lipophilic statins), or their physiologically acceptable forms for the preparation of an oral medicament, in a single tablet or by summation of the two individual substances, for the improvement of quality of life in patients suffering from multiple sclerosis, in whatever form it occurs, in case of intolerance of fluconazole;
 4. Use under control and prescription combinations referred to in paragraphs 1, 2 and 3 for the treatment of all forms of multiple sclerosis or neurodegenerative diseases characterized by a demyelinating form and/or intoxication or the presence of viruses such as the 'Epstein Barr virus or other members of the same family of herpesviruses; 